Physiology, Acute Phase Reactants

Introduction

Acute phase reactants (APR) are inflammation markers that increase or decrease in the patient’s serum during times of acute tissue injury or inflammation. They are also important mediators in the inflammatory process that is activated after such stress has been inflicted on the body. The APR can be classified as positive or negative depending on if their levels increase or decrease in the serum respectively. The most commonly measured positive APR include C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR). The negative APR include albumin, prealbumin, retinol-binding protein, and transferrin. In this concise review, we will focus on CRP, ESR, and procalcitonin (PCT), a novel, evolving biomarker that appears to be more useful to predict bacterial infections in certain organs. Clinically relevant other APR will be mentioned.

Cellular

If the body is impacted by noxious stimuli such as infection, trauma (physical and surgical), acute exacerbation of arthritis, among others, there is a triggering of certain pro-inflammatory cytokines including interleukin (IL)-6 (IL-6), IL-1, Tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (INF-gamma).[1],[2] These cytokines lead to a release of the AP proteins from the liver such as CRP and fibrinogen, ESR changes in the blood when the quantity or quality of red blood cells or fibrinogen and immunoglobulins increases, as fibrinogen increases with acute inflammation. IL-6 is the main triggering cytokine for the release of CRP. Increased procalcitonin (PCT) can be secreted following activation by IL-6, IL-1, and TNF-alpha by many cells; although, under normal conditions, it derives from the parafollicular (C cells) of the thyroid gland where it is converted to calcitonin. The cellular role of CRP is to function as an opso-phagocytic agent mopping up debris and delivering it to phagocytes such as macrophages.[2] CRP also activates complement in this role. On the other hand, serum amyloid A (SAA) another APP, functions as an inhibitor of many biological processes. These include inhibition of fever, platelet activation, mobilization of monocytes, and chemotactic effect on various immune cells.[1],[2]

Function

The main function of these APR is to halt and or attenuate the spread of an acute infection or the resultant exuberant inflammatory response by trapping the foreign material and modulating the activated biological processes. Many of the APR accomplish this by activating the complement system and hence the body’s cascading immune response. ESR is used to indirectly measure the amount of fibrinogen by determining the rate at which erythrocytes settle inside a vertical tube in 1 hour. The ESR level, unlike CRP only starts to rise within 24 to 48 hours. An increase in ESR can be indicative of acute inflammation which can be caused by tissue injury, ischemia, trauma, infectious diseases, and/or malignant neoplasms, for example, myeloma[3].

CRP is the prototypic marker of inflammation and has a higher sensitivity than ESR and is a direct measure of the inflammatory response. It was first discovered by Tillet and Francis in 1930 when they showed it reacted to the C-polysaccharide of Streptococcus pneumoniae in patients with pneumococcal pneumonia. It belongs to a highly conserved family of proteins referred to as pentraxins, which are typified by five protomers around a central pore and its half-life does not change between health and disease making the production rate the sole determinant of plasma concentrations.[1],[2] The normal range for CRP is between 2 to 10 mg/L. The CRP levels start to rise after 4 to 6 hours and peaks by 36 to 50 hours and can increase 100- to 1000-fold during acute inflammation.[3] The main functions of CRP are to help promote phagocytosis and the innate immune response against foreign infectious pathogens.[3]

Procalcitonin (PCT) a 14.5 kDa peptide can also be classified as an APP since secretion is stimulated by IL-6, IL-1, and TNF-like CRP and fibrinogen, and it increases with sepsis. However, it appears that secretion is not activated by gamma-interferon (produced mainly in response to viral infections) making it an attractive marker of bacterial infections.[4] To date, its greatest validated use is in the diagnosis of lower respiratory tract bacterial infections. It is more specific than CRP for diagnosis of sepsis and regulating antibiotic therapy. The normal procalcitonin levels are less than 0.1 ng/mL. If the PCT level is greater than 0.25 ng/ml and especially over 0.5 ng/ml then antibiotics are advised because a bacterial infection is likely, but if PCT is less than 0.1 ug/L, antibiotics are not recommended. Increased PCT level can be detectable 3 to 4 hours following the infection and peak around 6 to 24 hours, hence, the superiority over CRP as a marker of the AP response. An increase in PCT can also be seen with fungal and malarial infections as well.[4] However, PCT levels are also increased in other disorders such as renal disease and heart failure, cardiogenic shock and severe trauma, among others. Interpretation of these conditions can be challenging.

Mechanism

APR can be synthesized in 2 main pathways: hepatic synthesis and extrahepatic synthesis. In hepatic synthesis, the APR is created and secreted by hepatocytes, for example, CRP, fibrinogen, AAT, among others. In the extrahepatic synthetic pathway, neuroendocrine and parenchymal cells secrete PCT. In particular, the hepatic synthesis is triggered when the acute-phase genes are activated in the nucleus. The acute stimulus triggers a surge in IL-1, TNF, and IL-6 which result in the liver-producing CRP, fibrinogen, SAA, ferritin and other APPs.[1]

Related Testing

The best accepted clinical measures of acute inflammation are CRP and ESR. CRP has the advantage of being more sensitive and easily measured on automated platforms by nephelometry and turbidimetry in the majority of clinical laboratories and is a direct readout of the AP response. ESR is a more cumbersome test and an indirect measure APR proteins mainly fibrinogen. Both can provide results within hours. Other proteins that increase with acute inflammation include alpha-1antitrypsin (AAT), alpha-1-acid glycoprotein, alpha-2 macroglobulin, fibrinogen haptoglobin, and SAA. However, the quantification of these other proteins except fibrinogen, are not as well validated and standardized as CRP. However, in contrast to CRP, the increase in fibrinogen is around 2-fold only, and the rise is much later than CRP.[1]. The acute phase response is best appreciated on a serum protein electrophoresis that classically shows a decrease in serum albumin with a concomitant increase in alpha-1 and alpha-2 globulins with normal gamma-globulin levels. Measurement of the negative APP such as albumin, transferrin, prealbumin, and retinol-binding protein separately are not practical and cost-effective, and hence, discouraged in the assessment of the AP response.[5]

Pathophysiology

APRs are a major part of the overall process known as the acute phase response. These encompass many pathological processes that work together to help minimize and curtail tissue damage and enhance the repair process when trauma acutely challenges the body, for example, during a major motor vehicle accident or surgery, or after a serious acute infection like pneumonia, acute pyelonephritis, and acute meningitis.[1] The increase in AAT, alpha1chymotrypin and alpha2 macroglobulin are to function as anti-proteases and limit tissue damage. The increase in fibrinogen promotes clotting and haptoglobin scavengers any hemoglobin (iron) and prevents its loss. CRP promotes phagocytosis. Importantly there is also a negative APR, and these include decreases in serum albumin, transferrin, and prealbumin and retinol-binding protein since the synthesis of these proteins is inhibited by TNF, IL-1, and IL-6.[6]

Clinical Significance

It is important to realize that the APR are non-specific markers of inflammation. The tests used should be interpreted in conjunction with history, physical examination, and other laboratory tests and imaging. Their levels will be elevated during both acute and chronic inflammation. However, highest levels are attained in acute inflammation during an acute infection or after trauma resulting in CRP of 50 to 100 mg/L and ESR exceeding 50 mm per hour. The best recent advance relates to PCT that has been shown to predict bacterial infections of the lower respiratory tract (greater than 0.25 ng/ml) and confirming sepsis with levels greater than 0.5 ng/ml and guide antibiotic therapy. Medical professionals must wait to see if this test is validated for bacterial infections in other organ systems and accepted uniformly by guideline committees.[7]

Some of the APR like CRP are unique because they can be used in cardiovascular risk assessment for patients. It has also been shown in patients with acute coronary syndromes that elevated CRP levels assayed by the high sensitivity assay are indicative of poor cardiovascular prognosis. This includes increased mortality, post-myocardial infarction, and unstable angina, among others. In patients without ASCVD, a hsCRP between 3 to 20 mg/L, on 2 occasions at least 6 weeks apart, confers an increased risk for ASCVD provided a nidus for inflammation has been excluded.[8]